Metastatic prostate cancer: treatment

By definition, locally advanced and metastatic prostate cancer does not lend itself to radical treatment. Historically, most patients were represented with this form of the disease. Nevertheless, with the advent of the PSA screening era, the situation has changed for the better. However, despite this, there are a lot of men in the world who are diagnosed with the disease at a late stage.

Locally advanced prostate cancer involves spreading beyond the capsule without the presence of distant metastases and metastases in the regional lymph nodes. Metastatic prostate cancer means metastases in the lymph nodes, bone metastases or metastases in soft tissues

The main method of treating patients with locally advanced and metastatic forms of prostate cancer is hormonal treatment.

[1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12]

Hormonal treatment of prostate cancer

The effectiveness of hormonal treatment (operative castration and estrogen administration) in patients with metastatic prostate cancer was first shown in 1941.

Since this time, hormone therapy is one of the main methods of treating patients with advanced forms of prostate cancer. Currently, the use of hormone therapy is not limited to a group of patients with a metastatic form of the disease, using it as a monotherapy or as part of a multimodal treatment is also discussed for non-metastatic prostate cancer

Molecular basis of hormonal control of the prostate

Growth, functional activity and proliferation of prostate cells are possible with adequate androgen stimulation. The main androgen, circulating in the blood, testosterone. Not possessing oncogenic qualities, it is necessary for growth of tumor cells.

The main source of androgens in the male testicle, about 5-10% of androgens synthesize the adrenal glands. More than half of the testosterone is bound in the blood with a sex hormone, about 40% with albumin. Functionally active. The unrelated form of testosterone is only 3%.

After passive diffusion through the cell membrane, testosterone undergoes conversion to dihydrotestosterone under the action of the enzyme 5-a-reductase. Despite the fact that the physiological effects of testosterone and dihydrotestosterone are similar, the latter has 13 times more activity. The biological effect of both substances is realized by binding to androgen receptors located in the cytoplasm of cells. Later, the ligand-receptor complex moves to the nucleus of the cell, where it joins the specific promoter zones of the genes.

The secretion of testosterone is under the regulatory influence of the hypothalamic-pituitary-gonadal axis. The LHRH secreted by the hypothalamus stimulates the secretion of LH and FSH in the anterior pituitary. The action of LH is aimed at stimulating the release of testosterone by interstitial Leydig cells in the testicles.

Negative feedback from the hypothalamus is provided by androgenes and estrogens, formed from androgens as a result of biotransformation, circulating in the blood.

The regulation of the synthesis of androgens in the adrenal glands occurs through the axis of the hypothalamus (corticotropin-releasing factor) pituitary (adrenocorticotropic hormone) - adrenals (androgens) by the feedback mechanism. Almost all the androgens secreted by the adrenal glands are in an albumin-bound state, their functional activity is extremely low in comparison with testosterone and dihydrotestosterone. The level of androgens. Secreted by the adrenal gland, remains at the same level after bilateral orthhectomy.

Androgen deprivation of prostate cells is completed by their apoptosis (programmed cell death).

Creation of an androgen blockade

Currently, two main principles are used to create an androgen blockade:

• suppression of androgen secretion by the testicles due to drug or operative castration;
• inhibition of the action of androgen circulating in the blood at the level of receptor interaction in prostate cells (antiandrogens).

The combination of these two principles is reflected in the concept of "maximum (or complete) androgen blockade"

[13], [14], [15], [16], [17], [18], [19], [20]

Reduction of testosterone concentration in the blood (castration)

Bilateral orchiectomy

Bilateral orchiectomy in a short time leads to a decrease in testosterone levels of less than 50 ng / dL (based on the results of operations, this level is considered castration). 24 hours after operative castration, the concentration of testosterone is reduced by 90%. Taking this into account, bilateral orchiectomy is considered a "gold" standard for creating an androgen blockade, the effectiveness of all other methods is assessed in comparison with this operation.

It is possible to perform this operation on an outpatient basis under local anesthesia using one of two methods: complete orchectomy or subcapsular orchiectomy with preservation of the epididymis and the visceral leaf of the vaginal membrane. Subcapsular orchiectomy allows patients to avoid the negative psychological effect of the "empty" scrotum, however, the urologist needs to pay attention to the complete removal of the intrathecular tissue containing Leydig cells. With a technically correct operation, the results of the prosthetic and subcapsular orchiectomy are identical.

In recent years, we can note a decrease in the prevalence of operative castration associated with diatonics of the disease in the early stages, as well as the use of pharmacological methods of treatment equivalent in castration efficiency.

[21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31]

Estrogens

Estrogens have a multicomponent mechanism of action:

• decrease in LHRH secretion due to the feedback mechanism:
• inactivation of androgens;
• direct suppression of Leydig cell function:
• direct cytotoxic effect on the prostatic epithelium (proven only in vitro).

The most commonly used estrogen is diethylstilbestrol. The use of estrogens is limited due to the high level of cardiotoxicity and the risk of vascular complications (thrombogenic properties of estrogen metabolites), even at a low dose (1 mg), despite efficacy comparable with operative castration.

At present, interest in estrogen therapy is based on three positions.

• In comparison with LHRH receptor agonists, estrogens are of lower cost and do not lead to dangerous side effects (osteoporosis, cognitive disorders).
• Estrogens are highly effective in patients with androgen refractory prostate cancer.
• At present, new receptors for estrogens of the beta class have been discovered. Presumably related to oncogenesis in the prostate.

To prevent cardiovascular toxicity of estrogens, the use of the parenteral route of drug administration (to exclude the formation of toxic metabolites, due to the effect of the first passage through the liver), as well as cardioprotective drugs, is suggested. Nevertheless, studies have shown that the use of anticoagulants and antiplatelet agents for their angioprotective effect does not actually reduce the risk of tromboembolic complications.

[32], [33], [34], [35], [36], [37], [38]

Inhibitors of the releasing hormone

Agonists of the receptors of the releasing hormone (LHRH) (buserelin, goserelin, leuprorelin, triptorelmn) are synthetic analogues of LHRH. The mechanism of their action consists in the initial stimulation of LHRH receptors of the pituitary gland and the release of LH and FSH, which increase the production of testosterone by Leydig cells. After 2-4 weeks, the feedback mechanism suppresses the synthesis of pituitary LH and FSH, which leads to a decrease in blood testosterone levels before castration. Nevertheless, the use of LHRH receptor agonists does not allow this to be achieved in about 10% of the observations.

A meta-analysis of 24 large studies, including about 6,600 patients, showed that the lifespan of patients with prostate cancer under conditions of monotherapy with LHRH receptor agonists did not differ from that in patients who underwent bilateral orthochromia.

The initial "outbreak" of LH concentration, and accordingly of testosterone in the blood, begins 2 3 days after the injection of these drugs and lasts up to 10-20 days. Such an "outbreak" can lead to life-threatening aggravation of the symptoms of the disease, especially in patients with common forms. Among such symptoms, one should list the pain in the bones, the acute retention of urination, renal failure due to obstruction of the ureters, compression of the spinal cord, serious complications from the cardiovascular system due to the tendency to hypercoagulable. There are differences between the phenomena of "clinical outbreak" and "biochemical outbreak" (increase in PSA level). The most affected patients are the patients with a large amount of bone tissue lesions that are symptomatic (about 4-10% of patients with stage Ml disease).

When using LHRH-receptor agonists, it is necessary to simultaneously prescribe antandrogenic drugs, which prevents the described undesirable effects of elevated testosterone levels. Antiandrogens are used for 21-28 days.

For patients with a high risk of spinal cord compression, it is necessary to use the means leading to a rapid decrease in testosterone levels in the blood (operative castration, LHRH antagonists).

Releasing hormone receptor antagonists

The administration of LHRH receptor antagonists (cetrorelix) leads to a rapid decrease in testosterone levels due to blockade of LHRH receptors in the pituitary: within 24 hours after administration, LH concentration decreases to 84%. Considering this, there is no need to prescribe antiandrogenic drugs due to the absence of the "flash" phenomenon.

The effectiveness of monotherapy with LHRH antagonists is comparable to that of LHRH agonists in combination with antiandrogens.

The possibility of widespread use of drugs in this group complicates a number of facts. Most of the antagonists of LHRH receptors can cause serious histamine-mediated allergic reactions, including after a previous successful appointment. Considering this. These medications are prescribed for patients who refused operative castration, for which the remaining drug options for hormonal treatment are not possible.

Medical personnel monitor the patient within 30 minutes after the administration of the drug due to a high risk of allergic reactions.

Inhibitors of androgen synthesis

Ketoconazole is an oral antifungal drug that inhibits the synthesis of androgens by the adrenal glands and testosterone by Leydig cells. The effect after administration of the drug occurs very quickly, sometimes within 4 hours after the appointment: the effect of ketoconazole is also rapidly reversible, therefore a constant dosage regimen (400 mg every 8 hours) is required to maintain testosterone at a low level.

Ketoconazole is a fairly well tolerated and effective drug, it is prescribed to patients in whom hormone treatment of the first line was ineffective.

Despite the rapidly developing effect, prolonged treatment with ketoconazole in patients without concomitant hormonal modulation (surgical, drug castration) leads to a gradual increase in testosterone in the blood to normal values within 5 months.

At the moment, the use of ketoconazole is limited to a group of patients with androgen refractory prostate cancer.
Side effects of ketoconazole treatment: gynecomastia, lethargy, general weakness, liver dysfunction, visual impairment, nausea.
Given the suppression of adrenal function, ketoconazole is usually prescribed in combination with hydrocortisone (20 mg twice a day).

Antiandrogen treatment

Antiandrogens block intracellular receptors, possessing greater affinity than testosterone, thereby inducing apoptosis of prostate cells.

Orally prescribed antiandrogens are classified into two main groups:

• antiandrogens having a steroid structure (cyproterone, medroxyprogesterone);
• nonsteroidal antiandrogens (flutamide, bicalutamide, nilutamide).

Steroidal antiandrogens also have a suppressive effect on the pituitary gland, due to which the testosterone level decreases, whereas against the background of the use of non-steroid drugs, testosterone levels remain normal or slightly elevated.

[39], [40], [41], [42], [43], [44], [45], [46]

Steroidal antiandrogens

Ciproterone is one of the first and most famous drug in the group of antiandrogens with a direct blocking effect on androgen receptors, which also reduces the concentration of testosterone in the blood due to central suppression (progestagenic properties). Ciproterone is taken orally, the recommended dose is -100 mg 2-3 times a day.

In the monotherapy regime, the effectiveness of cyproterone is comparable to flutamide.

Side effects of cyproterone are caused by hypogonadism (decreased libido, impotence, fatigue), up to 10% of patients may experience severe complications from the cardiovascular system, which limits the use of this drug. Gynecomastia is a side effect of less than 20% of men taking cyproterone. In the literature, rare observations of fulminant hepatotoxicity are mentioned.

Non-steroidal anti-androgens ("pure" antiandrogens)

Blocking of androgen receptors by antiandrogens leads to an increase in the concentration of LH and testosterone by approximately 1.5 times due to the mechanism of positive feedback to the hypothalamus. The absence of a drop in testosterone levels avoids a number of side effects caused by hypogonadism: loss of libido, poor health, osteoporosis.

Despite the fact that direct comparison of the three drugs used (bicalutamide, flutamide, nilutamide) was not performed in monotherapy mode, they practically do not differ in the severity of pharmacological side effects: gynecomastia, mastodynia, hot flushes. However, Bnalutamyl is somewhat safer in comparison with Nilutamide and Flutamide.

Gynecomastia, mastodynia, hot flushes are caused by peripheral aromatization of excess testosterone to zestradiol.
Toxicity to the gastrointestinal tract (mainly diarrhea) is more typical for patients taking flutamyl. Hepatotoxic (from the lungs to fulminant forms) to some extent all anti-androgens, in this regard, periodic monitoring of liver function is necessary.

Despite the fact that the mechanism of the action of "pure" antiandrogens does not imply a reduction in testosterone, long-term preservation of erectile function is possible only for every fifth patient.

Nilutamide. To date, there are no studies on the use of this drug for monotherapy of prostate cancer in comparison with other anti-androgens or castration.

A recent study of the use of nilutamide as a second-line drug for the treatment of patients with androgen refractory prostate cancer showed a good response to therapy.

Non-pharmacological side effects of nilutamide include visual impairment (long adaptation to darkness after bright light - about 25% of patients), 1% of patients may have interstitial pneumonia (up to lung fibrosis), hepatotoxicity, nausea, alcohol sensitization.

The half-life of nilutamide is 56 hours. Elimination occurs with the participation of the liver cytochrome P450 system. The recommended dosage of the drug is 300 mg once per day for 1 month, then maintain a dose of 150 mg once a day.

Flutamide is the first drug from the family of "pure" antiandrogens. Flutamide is a prodrug. The half-life of the active metabolite, 2-hydroxyflutamide, is 5-6 hours, this necessitates a 3-fold daily dosage regimen (250 mg 3 times a day). Excretion of 2-hydroxyflutamide is performed by the kidneys. Unlike steroidal antiandrogens, side effects due to fluid retention in the body or thromboembolic complications are absent

The use of flutamide as monotherapy in comparison with orchiectomy and maximum androgen blockade does not affect the life expectancy of patients with advanced forms of prostate cancer.

Non-pharmacological side effects - diarrhea, hepatotoxicity (rarely - fulminant forms).

Bicalutamide is a non-steroidal antiandrogen with a long half-life (6 days). Bicalutamide is prescribed once a day, it is characterized by a high compliance.

Bicalutamide has the greatest activity and the best safety profile among the "pure" antiandrogens. The pharmacokinetics of the drug are not affected by age, renal and hepatic insufficiency of mild and moderate severity.

In most patients, the level of testosterone in the blood remains unchanged. The use of bicalutamide in a dose of 150 mg in patients with locally advanced and metastatic forms of the disease is comparable in effectiveness to surgical or drug castration. At the same time, he has much better tolerability from the standpoint of sexual and physical activity. However, the frequency of gynecomastia (66.2%) and mastodynia (72.8%) in this group of patients is high.

The use of bicalutamide is not recommended for patients with limited forms of the disease, since it is associated with a decrease in life expectancy. Response to hormonal treatment

After prescribing drugs that cause androgen deprivation. The effect is more or less evident in most patients. Given that the target for hormonal treatment is androgen-sensitive prostate cells, an incomplete or erased effect indicates the presence of a population of androgen-refractory cells. PSA as a biological marker has a certain predictive ability in response to hormonal treatment. For example, in patients with the dynamics of PSA decline of more than 80% after 1 month of hormonal therapy, life expectancy is much greater. Also predictive abilities are such indicators as nadir PSA and testosterone level before the start of treatment.

The probability of switching to androgen refractory form of prostate cancer within 24 months is 15 times higher in patients in whom the level of PSA on the background of hormonal treatment has not reached undetectable values in the blood. An increase in Gleason's score by 1 point increases the probability of development of androgen refractive cancer by 70%.

When calculating the probability of disease progression, it is necessary to take into account the dynamics of the growth of the amount of PSA before the start of treatment and decrease in the level of hormonal treatment. The rapid increase in the level of PSA before the start of treatment and its slow decrease are prognostically unfavorable factors regarding the life expectancy of patients.

Virtually all patients without exception, clinically no longer responding to hormonal treatment (transition to androgen refractory form of prostate cancer), must be in the state of androgen blockade, because remaining refractory to the absence of androgens, prostate cells are sensitive to them. According to some authors, the predictors of life expectancy in this group of patients are the overall somatic status, LDH activity and alkaline phosphatase in the blood serum, the level of hemoglobin and the severity of response to second-line treatment. Also predictors are a 50% reduction in PSA levels against chemotherapy, the presence or absence of internal disease, the baseline PSA level.

Combined hormonal treatment

[47], [48], [49], [50], [51], [52], [53]

Minimal androgenic blockade (peripheral androgen blockade)

It assumes simultaneous use of a 5-a-reductase inhibitor and a non-steroidal anti-androgen drug. Advantages of this treatment scheme - the preservation of quality of life and sexual function at an acceptable level

Until the final results of clinical trials are obtained, the use of this regimen is not recommended.

Maximum androgen blockade

Given that after surgical or drug castration, a certain low level of androgens secreted by the adrenal gland is maintained in the blood, the concept of maximal androgenic blockade (a combination of castration and antiandrogens) is interesting.

Nevertheless, the clinical benefit from such a regimen is questionable in the context of routine clinical practice.

Systematic reviews and meta-analyzes of recently completed large-scale studies have shown that 5-year survival of patients against the background of maximum androgenic blockade is higher than that of patients receiving monotherapy (castration) by less than 5%.

The use of maximum androgen blockade in patients with advanced forms of prostate cancer is associated with a high frequency and severity of side effects, as well as a significant increase in the cost of treatment.

Continuous or intermittent hormonal treatment

After some time after the start of treatment aimed at deprivation of androgens, cancer cells in the prostate are given an androgen refractory status: the absence of androgens no longer serves as a trigger for apoptosis for certain cell lines.

The concept of intermittent hormonal treatment is based on the assumption that. That with the abolition of hormonal therapy, the further development of the tumor is due to differentiation of the androgen-sensitive cell line. Thereby permitting repeated use of the phenomenon of androgen withdrawal. This is why the passage of prostate cancer into androgen refractory may be postponed in time.

In addition, intermittent hormonal treatment can improve the quality of life of patients between the therapeutic cycles, as well as reduce the cost of treatment.

The equivalence of intermittent and continuous approaches in the treatment of patients with metastatic prostate cancer, as well as relapse after radical treatment has been confirmed by a number of clinical studies.

In one study, nadir PSA, achieved after 9 months of introductory hormonal treatment, served as an independent prognostic factor in the life expectancy of patients. The decrease in PSA after an introductory treatment cycle of less than 0.2 ng / ml, less than 4 ng / ml, more than 4 ng / ml, corresponded to the average life expectancy of patients with advanced forms of prostate cancer 75 months, 44 months and 13 months, respectively.

[54], [55], [56], [57], [58], [59], [60], [61]

Immediate or delayed hormonal treatment

At present, there is no clear opinion regarding the timing of the onset of hormonal treatment. The previously proposed regimens suggest the possibility of initiating therapy both immediately after the failure of radical treatment, and after the appearance of clinical signs of metastasis.

This situation is related to the lack of the opportunity to extrapolate the results of clinical studies because of their limitations in everyday practice.

The course of prostate cancer and the use of hormonal treatment characterizes a number of facts.

First, even in men, intact in the hormonal plan, the progression of prostate cancer takes a long time. Studies show that after a recurrence of prostate cancer before metastasis is 8 years. 5 more years from the moment of metastasis to the death of the patient.

Secondly, in 20% of men against the background of hormonal treatment for prostate cancer, the cause of death will not be associated with this disease, while the rest of the cause of death - the transition of cancer into a hormone-refractory form. One prospective, randomized trial shows. That in 10 years after the beginning of hormonal treatment in a group of patients, only 7% remained alive. The average life expectancy after the beginning of hormonal therapy is 4.4 years, after 8 years, about 4.5% of patients remain alive.

Thirdly, hormonal treatment is by no means harmless. Without taking into account the side effects of therapy, men receiving hormone treatment for prostate cancer grow old much faster, leading to an early death from causes related to age.

In this regard, a reasonable approach to the timing of the onset of hormonal treatment in patients with prostate cancer is needed.

At present, there is a definite position regarding hormonal treatment in patients with localized prostate cancer. The life expectancy of this group of patients under conditions of hormonal therapy is much lower than that for a deferred treatment strategy. This is due to the fact. That the appointment of hormonal treatment leads to a rapid aging of those patients who have a risk of dying from prostate cancer and so low.

In this situation, the appointment of hormonal treatment should be discussed in detail with the patient himself.

Prostate cancer with metastases in the regional lymph nodes

Immediate and delayed treatment with hormonal drugs in patients with stage pNl-3 disease (histology after RP) was assessed by the Eastern Cooperative Oncology Group (ECOG) and the European Bladder Cancer Research and Treatment Organization.

The first study showed that after 7.1 years of follow-up, mortality in the group of patients with deferred treatment exceeded that in the group of patients with immediate hormonal therapy. Subsequent update of information on this study showed that the average life expectancy with immediate treatment is 13.9 years compared to 11.3 years in patients with delayed therapy of the disease. Despite the high mortality from non-prostate cancer-related causes (55 versus 11% in the deferred therapy group), immediate application of hormonal treatment had an undoubted clinical advantage.

Nevertheless, the clear interpretation and objectivity of the results of this study is limited in connection with a small group of studied patients (100 men), the lack of calculation of the correlation of life expectancy and the degree of differentiation of tumor cells, the absence of a group of patients receiving only hormonal treatment.

A study performed by the European Bladder Cancer Research and Treatment Group (302 patients with stage pN1-ZM0 without primary treatment for the main focus) showed that the average life expectancy of patients receiving hormone treatment immediately after diagnosis was 7.8 years in comparison with 6.2 years in the group of patients with delayed therapy.

Locally and asymptomatic metastatic prostate cancer

In one of the studies of the Medical Research Council of the Prostate Cancer Working Party Investigators Group (934 patients), started in 1997 (the results were evaluated in 2004), it was shown that for patients in this group, the immediate administration of hormonal treatment has a positive effect, specific life expectancy, and on the severity of symptoms associated with prostate cancer. Nevertheless, against the background of long-term follow-up of patients, the overall life expectancy did not change significantly, depending on the time of onset of hormonal treatment.

Conclusions

• Hormonal treatment can not be used in men with localized prostate cancer, since this does not lead to an increase in overall life expectancy, only worsening the mortality rate due to other causes.
• For patients with locally advanced, asymptomatic metastatic and symptomatic but not prostate cancer, the use of immediate hormonal treatment leads to a significant increase in cancer-specific life expectancy, without affecting overall survival.
• In patients with prostate cancer with stage N + after RP, the average life expectancy is significantly higher with the use of immediate hormonal treatment, for patients without primary treatment, an increase in life expectancy is not significant.

Observation of patients with prostate cancer receiving hormone treatment

• Patients are examined at 3 and 6 months after the start of treatment. The minimal volume of the examination: the determination of PSA level, digital rectal examination and careful evaluation of the symptoms, aimed at obtaining evidence of the effectiveness of treatment and its side effects.
• Observation of the patient is carried out on an individual basis, taking into account the symptoms, prognostic factors and the prescribed treatment.
• Patients with stage M0 disease with a good response to treatment are examined (symptom score, digital rectal examination, PSA determination) every 6 months.
• Patients with stage M1 disease with a good response to treatment are examined (symptom score, digital rectal examination, PSA determination, general clinical blood test, creatinine, alkaline phosphatase) every 3-6 months.
• In cases where there are signs of progression of the disease or a poor response to treatment, an individual approach to monitoring is needed.
• Routine use of instrumental examination methods (ultrasound, MRI, CT, osteoscintigraphy) with stable patient status is not recommended.

Complications of hormonal treatment of prostate cancer

The side effects of hormonal treatment of patients with cancer have been known for a long time (Tables 33-19). Some of them to Cosine negatively affect the quality of life of patients, especially young ones, while others can significantly increase the risk of health problems associated with age-related changes.

Side effects of hormonal treatment

Castration
Side effects	Treatment / Prevention
Decreased libido	No
Impotence	Inhibitors of phosphodiesterase-5, intracavernous injection, therapy with local negative pressure
Hot flushes (55-80% of patients)	Cyproterone, clonidine. Venlafaxine
Gynecomastia, mastodynia (50% maximal androgen blockade, 10-20% castration)	Preventive radiation therapy, mammectomy, tamoxifen, aromatase inhibitors
Weight gain	Physical exercises
Muscle weakness	Physical exercises
Anemia (severe in 13% of patients with maximal androgen blockade)	Preparations of erythropoietins
Osteopenia	Exercise, a preparation of calcium and vitamin D, bisphosphonate
Cognitive Disorders	No
The pathology of the cardiovascular system (myocardial infarction, heart failure, stroke, deep vein thrombosis, pulmonary embolism)	Parenteral administration, anticoagulants
Antiandrogens
Steroidal
Pharmacological side effects: decreased libido, impotence, rarely gynecomastia
Non-pharmacological
Non-steroidal
Pharmacological side effects: mastodynia (40-72%), hot flashes (9-13%), gynecomastia (49-66%)	Preventive radiation therapy, mammectomy, tamoxifen, aromatase inhibitors
Non-pharmacological

[62], [63], [64], [65], [66], [67], [68], [69], [70], [71]

Osteoporosis

The probability of bone fractures in the group of patients receiving hormone treatment for prostate cancer is much higher than in the population. Hormonal treatment for 5 years increases the risk of fractures 1.5 times, over 15 years - more than 2 times.

Diagnosis of oteoporosis consists in performing X-ray absorptiometry to determine the bone density of the femur, performed by all men who plan hormonal treatment.

To increase the mineral density allow regular exercise, quitting, the use of calcium and vitamin D. To prevent osteoporosis, use drugs from the group of bisphosphonates. Bisphosphonates (preferably zoledronic acid) should be given to all men with confirmed osteoporosis.

Hot flushes

Hot flushes are a subjective sensation of heat in the upper body and head. Objectively accompanied by excessive sweating.

Presumably, the cause of this complication is an increase in the tone of the adrenergic centers in the hypothalamus, pathological abnormalities in the beta-endorphin concentration, the effect of peptides associated with the calcitonin gene on the centers of the hypothalamic thermoregulation.

Treatment of hot flushes should be performed only in patients who are not tolerant of this side effect of hormonal treatment.

Cyproterone (initial dose 50 mg / day further titration up to 300 mg / day) due to its progestagenic effect significantly reduces the frequency of hot flashes.

The use of estrogens (diethylstilbestrol in a minimal dose or estradiol in a transdermal form) is most effective (efficacy over 90%). Nevertheless, severe mastodynia and thromboembolic complications due to estrogen administration, as a rule, limit their use.

Antidepressants (in particular, selective serotonin reuptake inhibitors, venlafaxine) reduce the incidence of hot flashes by 50%.

Sexual function

About 20% of patients receiving hormone treatment, in one way or another retain sexual function. Libido is more adversely affected. Only about 5% of patients retain a high level of sexual interest.

In a certain group of patients, oral phosphodiesterase inhibitors of type 5, intracavernous injections of alprostadil are effective.

Gynecomastia

Gynecomastia is caused by an excess of estrogens in the body (estrogen therapy, peripheral transformation of androgens to estrogens in the treatment of antiandrogenic drugs); up to 66% of patients taking bicalutamide in a dose of 150 mg. They detect gynecomastia, of which up to 72% indicate pain in the mammary glands.

To prevent or eliminate painful gynecomastia, the possibility of using radiation therapy (10 Gy) was investigated, which is ineffective if gynecomastia has already manifested itself. Liposuction and mastectomy are also used to treat this complication. To reduce the severity of mastodin use tamoxifen.

Anemia

Normochromic, normocytic anemia is found in 90% of patients receiving hormone treatment for prostate cancer. As a rule, a decrease in hemoglobin content of about 10% is noted. The concentration of hemoglobin decreases after 1 month. In most men (87%) returns to baseline values after 24 months due to compensatory mechanisms.

For the treatment of anemia, regardless of the etiology, recombinant erythropoietin preparations are used. Anemia is reversible after the abolition of hormone therapy for a year.

[72], [73], [74]